Field of the Invention
The present application relates to medicinal chemistry, in particular to cyclohexane compounds or stereoisomers or salts thereof, and more particularly to cyclohexane derivatives of formula IB or formula I, or stereoisomers or salts thereof, and preparation and use thereof.
Description of Related Art
Mental disorders have been the diseases that seriously affect human health with the rapid social development, the increased pace and stress from lives, which leads to bad consequences for the patients and their families. Suicide, deficiency of medical care and high risk of complications (for example, malnutrition, insufficient exercises, obesity and smoking) are contributors to shortened average life expectancy of patients. Many studies have shown that mental disorders are associated with various neurotransmitters and receptor dysfunction in the central nervous system; for example, monoamine neurotransmitters in brain, especially dopamine (DA) system and 5-hydroxytryptamine (5-HT) system are closely related to the normal mental activities. Dysfunction of DA and 5-HT systems can lead to a variety of neuropsychiatric diseases, such as schizophrenia, depression, neuropathic pain, mania, anxiety and Parkinson's disease.
The Patent WO 9967206 A1 discloses an application of a cyclohexane derivative in the treatment of pain diseases, but is silent about the application in mental diseases, especially for dopamine D2/D3 receptors.
The Patent CN 1829703 A discloses an application of a cyclohexane derivative having (thio) carbamoyl side chain in the modulation of dopamine receptor-related disorders, in which the D2/D3 antagonist and 5-HT1A partial agonist Cariprazine (Cariprazine, RGH-188) jointly developed by Forest Laboratories and Gedeon Richter for the treatment of schizophrenia, mania and depression have now passed clinical trials and entered the registration and approval stage. Cariprazine has a formula as shown below, and has affinities (Ki values) of 0.72 nmol, 0.08 nmol and 3.42 nmol for D2/D3 receptors and 5-HT1A, respectively, i.e. it does have a certain selectivity to D2/D3 receptor, but still not ideal. It is therefore possible that such drug clinically has less chance (nearly 5% probability at a dose of 3 mg) on the occurrence of the cathisophobia, extrapyramidal reaction as these side effects are associated with excessive blocking of the D2 receptor.

In light of the above problems, Cariprazine is further structurally modified in Patent CN 103130737 A so as to achieve higher selectivity to the D3 receptor.
However, given the various causes for mental diseases, there remains a need for the development of the medicaments to meet the requirement from the treatment of mental diseases, although the compounds as described above function well against schizophrenia.